Retinoids, which are the compounds comprising vitamin A and its derivatives, play important roles in a variety of biological phenomena. More particularly, retinoids are important for vision, hematopoiesis, bone development and pattern formation during embryogenesis. Retinoids also exhibit antiproliferative activities in certain biological contexts.
Retinoids also have been used extensively as pharmaceutical agents for treating various malignant and non-malignant skin diseases. Malignant skin diseases therapeutically responsive to retinoids include squamous cell carcinoma, actinic keratoses, basal cell carcinoma and Kaposi's sarcoma. Additionally, retinoids are potentially useful as pharmacological agents for the treatment of various epithelial cancers (Peck and DiGiovanna, "Synthetic Retinoids in Dermatology") in The Retinoids, 2nd ed., pp 631-658 (1994); Boehm et al., Exp. Opin. Invest. Drugs 4:593 (1995); Nagpal and Chandraratna, Curr. Pharm. Design 2:295 (1996)). Examples of non-malignant skin diseases therapeutically responsive to retinoids include psoriasis and acne. In spite of the demonstrated utility of this class of pharmacological agents, the molecular basis of retinoid action in skin and various cancers is poorly understood.
Two families of nuclear receptors, called the retinoic acid (RA) receptors (RAR-.alpha., -.beta. and -.gamma.) and the retinoid X receptors (RXR-.alpha., -.beta. and -.gamma.), mediate pharmacological and physiological retinoid signalling (Chambon, Sem. in Cell Biol. 5:115 (1994); Mangelsdorf et al., "The Retinoid Receptors" in The Retinoids, 2nd ed., pp 319-349 (1994); Boehm et al., Exp. Opin. Invest. Drugs 4:593 (1995); Nagpal and Chandraratna, Curr. Pharm. Design 2:295 (1996)). RARs and RXRs, which belong to the superfamily of steroid/thyroid/vitamin D.sub.3 nuclear receptors, readily heterodimerize in vitro (for references see, Nagpal and Chandraratna, Curr. Pharm. Design 2:295 (1996)) and function as heterodimers in vivo (Nagpal et al., EMBO J 12:2349 (1993)). These receptors are ligand-dependent transcription factors which activate the expression of retinoid responsive genes by cooperative action of their activation functions. These activation functions are called AF-1, a ligand-independent activation function, and AF-2, a ligand-dependent activation function (Nagpal et al., EMBO J. 12:2349 (1993)).
The two families of retinoid receptors differ from each other with respect to the ligands that bind and activate the receptors. All-trans-RA (RA) binds and activates the RAR family of receptors. A different ligand, 9-cis-RA (9C-RA), binds and activates both the RARs and members of the retinoid X receptor (RXR) family. The retinoid called AGN 190168 (Tazarotene/ethyl 6-[2-(4,4) dimethyl-thiochroman-6-yl] ethynyl-nicotinate) is one example of an RAR-.beta./.gamma. selective synthetic retinoid having therapeutic utility. More specifically, this synthetic retinoid can be administered topically to dramatically improve the symptoms associated with psoriasis.
Only a small number of retinoid-inducible gene products have been identified to date. Of these, the gene product encoding a cellular retinoic acid binding protein, called CRABP II, is the only marker known to be induced in vivo by RA in non-diseased skin (Elder et al., J Invest. Dermatol. 100:356 (1993)). Interestingly, CRABP II expression was down-regulated by RA in submerged keratinocyte cultures (Elder and Cromie, J. Toxicol.--Cut. & Ocular Toxicol. 12:173 (1993)) and was overexpressed in cells of tissues that exhibited a psoriatic phenotype (Didierjean et al., Biochem. Biophys. Res. Comm. 180:204 (1991)). Those having ordinary skill in the art will appreciate that psoriasis is a hyperproliferative and inflammatory condition of the skin (Krueger and Duvic, J Invest. Dermatol. 102:14S (1994)) which clinically responds to retinoid treatment (Esgleyes-Ribot et al., J Am. Acad. Dermatol. 30:581 (1994); Weinstein, Brit. J Dermatol. 135(Suppl. 49):32 (1996)).
Two novel genes, called Tazarotene-induced gene 1 (TIG1) and Tazarotene-induced gene 2 (TIG2), were recently identified by virtue of their inducible expression in skin raft cultures treated with Tazarotene (Nagpal et al., J Invest. Dermatol. 106:269 (1996); Nagpal et al., submitted (1997)). TIG1 was also shown to be induced by Tazarotene in foreskin keratinocyte and fibroblast cultures. Significantly, both TIG1 and TIG2 were induced in vivo by topical treatment of psoriatic lesions with Tazarotene.
Herein we disclose the discovery and utility of a novel retinoid-induced polynucleotide that is unrelated to either TIG1 or TIG2.